The goals of the current application are to either develop or apply methods to study the dopaminergic system with SPECT (single photon emission computed tomography) and microdialysis to assess the neurochemical alterations in the brain which are induced by chronic cocaine administration. During the previous funding cycle, we successfully implemented SPECT methods (first in monkeys and then in humans) to quantify dopamine D2 receptors and dopamine transporters; to combine i.v. amphetamine,challenge with D2 receptor imaging as an indirect measure of synaptic dopamine levels; and to combine microdialysis with SPECT imaging to provide direct measurements of extracellular dopamine levels. Two PET studies have recently demonstrated significant reductions in D2 receptors in non-detoxified male cocaine abusers as compared to healthy male controls using [18F]N-methylspiroperidol (Volkow et al., 1990 and 1993). These alterations in D2 receptors could have been confounded by abnormal cerebral blood flow in the cocaine addicts. We propose to compare levels of D2 receptors in active cocaine abusers and healthy controls using an equilibrium method which is not influenced by alterations of blood flow (Specific Aim #1). In addition, the D2 receptor imaging will be combined with on- going studies of the dopamine transporter to provide both pre- and postsynaptic measures of dopaminergic transmission in cocaine dependence. Since age and gender may have important effects on D2 receptors, equal numbers of males and females will be studied and cocaine addicts and controls will be individually matched for age. In addition, we will measure potential changes in D2 receptors during states of acute vs. sustained drug abstinence (Specific Aim #2). In the animal studies, we will use SPECT imaging of the D2 receptor before and after depletion of DA by AMPT (alpha-methyl-para-tyrosine) and reserpine to examine D2 receptor occupancy induced by basal levels of endogenous DA (Aim #3). In addition, we will examine the ability of the ability of both SPECT receptor imaging and microdialysis to measure sensitization induced by chronic amphetamine administration (Aim #4). The animal studies have been designed so that, if they generate positive results, we will have gathered critical data to extend these paradigms to study human subjects who abuse cocaine.